title: Chemical-physical analysis of a tartrate model compound for TACE inhibition.
abstract: We have synthesized and done an extensive chemical-physical analysis of the behavior of a new compound, named MBET306, a synthetic precursor of the recently discovered tartrate-based inhibitors of the protein Tumor Necrosis factor-α Converting Enzyme (TACE). Experimental and theoretical data have shown that in water solution MBET306 is overwhelmingly found as a monoanion at physiological pH, in a conformation that differs substantially from that detected in the known co-crystal structures of MBET306 derivatives bound to TACE. The body of collected experimental and theoretical data indicates that the monoanionic species binds Zn(ii) inducing a strong stabilization of the crystal-like arrangement of the central tartrate zinc-binding group, lending support for a two step TACE docking mechanism via a zinc-bound intermediate. The thorough chemical-physical characterization of the conformational behavior of free and zinc-bound MBET306 in water bulk solution opens new avenues for the rational drug design of tartrate-based highly specific TACE inhibitors.
authors.affiliation: Department of Chemistry/CSGI, University of Florence, Italy. caminati@unifi.it.
authors.forename: Martina
authors.initials: M
authors.lastname: Banchelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Guardiani
authors.forename: Eleonora
authors.initials: E
authors.lastname: Tenori
authors.forename: Stefano
authors.initials: S
authors.lastname: Menichetti
authors.forename: Gabriella
authors.initials: G
authors.lastname: Caminati
authors.forename: Piero
authors.initials: P
authors.lastname: Procacci
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013644:Tartrates / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
chemical_list: C000588525:2,3-dihydroxy-4-oxo-N-((R)-1-phenylethyl)-4-(pyrrolidin-1-yl)butanamide; D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D013644:Tartrates; D014867:Water; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D015032:Zinc; C029768:tartaric acid